School of Chemical and Biomedical Engineering, Nanyang Technological University, 70 Nanyang Drive, Singapore 637457, Singapore.
J Am Chem Soc. 2020 Apr 15;142(15):7075-7082. doi: 10.1021/jacs.0c00659. Epub 2020 Apr 1.
Real-time imaging of immunoactivation is imperative for cancer immunotherapy and drug discovery; however, most existing imaging agents possess "always-on" signals and thus have poor signal correlation with immune responses. Herein, renal-clearable near-infrared (NIR) fluorescent macromolecular reporters are synthesized to specifically detect an immunoactivation-related biomarker (granzyme B) for real-time evaluation of cancer immunotherapy. Composed of a peptide-caged NIR signaling moiety linked with a hydrophilic poly(ethylene glycol) (PEG) passivation chain, the reporters not only specifically activate their fluorescence by granzyme B but also passively target the tumor of living mice after systemic administration. Such granzyme B induced signals of the reporters are validated to correlate well with the populations of cytotoxic T lymphocytes (CD8) and T helper (CD4) cells detected in tumor tissues. By virtue of their ideal renal clearance efficiency (60% injected doses at 24 h postinjection), the reporters can be used for optical urinalysis of immunoactivation simply by detecting the status of excreted reporters. This study thus proposes a molecular optical imaging approach for noninvasive evaluation of cancer immunotherapeutic efficacy in living animals.
实时免疫激活成像对于癌症免疫治疗和药物发现至关重要；然而，大多数现有的成像剂具有“始终开启”的信号，因此与免疫反应的信号相关性较差。在此，合成了可肾脏清除的近红外（NIR）荧光高分子报告物，以特异性检测免疫激活相关生物标志物（颗粒酶 B），用于实时评估癌症免疫治疗。该报告物由肽笼封的 NIR 信号部分与亲水性聚乙二醇（PEG）钝化链连接而成，不仅可以通过颗粒酶 B 特异性激活其荧光，而且在全身给药后还可以被动靶向活鼠的肿瘤。已验证此类报告物的颗粒酶 B 诱导信号与肿瘤组织中检测到的细胞毒性 T 淋巴细胞（CD8）和辅助性 T 细胞（CD4）细胞的群体密切相关。由于其理想的肾脏清除效率（注射后 24 小时内 60%的注射剂量），报告物可通过检测排泄报告物的状态，用于免疫激活的光学尿液分析。因此，该研究提出了一种分子光学成像方法，用于在活体动物中无创评估癌症免疫治疗的疗效。
